Dr. Blewitt has shown that inhibiting SMCHD1 allows several important protein-coding genes in the PWS to be expressed, but the effect is incomplete. Here she will determine the chromosomal landscape in the PWS region on the maternal chromosome and evaluate how that landscape changes when SMCHD1 is missing, paving the way for more efficient maternal gene activation to treat PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
People without PWS normally express a cluster of genes inherited from their father; the copy from their mother is switched off. PWS occurs essentially because the copy from the father is absent, but as in people without disease, the maternal copy is switched off. Therefore, a potential therapy for PWS is to awaken the maternal copy of these genes by inhibiting factors that normally silence these genes on the maternal copy. SMCHD1 is one such factor, that we discovered more than 10 years ago, and have since shown in mouse models that it switches off several of the genes in PWS cluster. Our latest data shows that the same holds true in human cells, where removing SMCHD1 results in several genes in the PWS cluster being switched back on. Thus, inhibiting SMCHD1 is a potential new treatment for PWS. Importantly, targeting SMCHD1 would treat the cause of PWS, and thus have the best chance of most effectively treating the wide array of symptoms experienced by patients. This will offer significant advantage to current treatments that can only mitigate individual symptoms and are associated with numerous side effects precluding their use by all PWS patients.
Our preliminary data provide compelling evidence that targeting SMCHD1 is a valid consideration for PWS treatment. We are developing world-first chemicals that inhibit SMCHD1 function, which can be turned into new therapeutics. Therefore, it is timely to study how we might best employ such chemicals in the future to treat PWS. To best do this, we will investigate how SMCHD1 works to switch off the PWS genes. This is an area where we are experts and uniquely possess the required tools. We know that proteins involved in switching genes off usually work together in a hierarchy. Understanding this hierarchy is beneficial firstly to uncover the underlying biological mechanisms involved in switching PWS genes off. Equally importantly, knowledge of the hierarchy can reveal additional avenues for therapeutic intervention.
Our data show that when SMCHD1 is removed, the PWS genes are not switched on in every cell. Furthermore, only around half the genes in the PWS cluster are switched on upon removal of SMCHD1. These data suggest that SMCHD1 collaborates with other factors to switch off the PWS maternal allele. Here we will test which other factors SMCHD1 collaborates with, to reveal how we might best activate the PWS genes in patients. Such experiments have never been performed before for SMCHD1 and they will allow a more complete understanding of where this protein sits amongst the other regulators of the cluster. Importantly our data will allow us to specifically consider whether combination therapy, with drugs inhibiting SMCHD1 and the other factors SMCHD1 works with, may be beneficial for PWS patients in the future.
If our application is successful, based on the data generated in this project, we would trial combination therapies in PWS patient-derived cells to achieve optimal gene activation with minimal side effects. Therefore, this work is laying the foundation for therapeutic development targeting the underlying genetic cause of PWS, which is desperately needed by patients and families.
Marnie Blewitt, Ph.D.
Walter and Eliza Hall Institute of Medical Research
Marnie Blewitt, PhD